论文标题

受体配体系统的代数研究:剂量反应分析

Algebraic study of receptor-ligand systems: a dose-response analysis

论文作者

Sta, Léa, Adamer, Michael, Molina-París, Carmen

论文摘要

对受体配体系统的研究通常依赖于其剂量反应(或浓度效应)曲线的分析,该曲线量化了在结合其特定细胞表面受体时诱导的配体浓度与生物学效应(或细胞反应)之间的关系。在假设生物学效应与配体结合受体数量成正比的假设下,已经开发了受体配体系统的数学模型来计算剂量反应曲线。给定剂量反应曲线,已经定义了两个数量(或指标)来表征所考虑的配体受体系统的性质:振幅和效力(或半最大有效浓度,并用EC $ $ _ {50} $表示)。幅度和EC $ _ {50} $都是药物动态建模中常用的关键数量,但是对这两个指标的行为进行了全面的数学研究仍然很出色。对于称为细胞因子受体的大型(且重要的)家族,我们仍然不知道幅度和EC $ _ {50} $如何取决于受体拷贝数。在这里,我们利用代数方法(Gröbner基础)来研究大量受体配体模型的这些指标,重点是细胞因子受体。特别是,我们介绍了一种基于白介素-7(IL-7)受体的两个激励示例,以计算振幅和EC $ _ {50} $的分析表达式。然后,我们将方法扩展到更广泛的受体配体系统,具有外部激酶的顺序受体 - 配体系统,并提供了一些示例。

The study of a receptor-ligand system generally relies on the analysis of its dose-response (or concentration-effect) curve, which quantifies the relation between ligand concentration and the biological effect (or cellular response) induced when binding its specific cell surface receptor. Mathematical models of receptor-ligand systems have been developed to compute a dose-response curve under the assumption that the biological effect is proportional to the number of ligand-bound receptors. Given a dose-response curve, two quantities (or metrics) have been defined to characterise the properties of the ligand-receptor system under consideration: amplitude and potency (or half-maximal effective concentration, and denoted by EC$_{50}$). Both the amplitude and the EC$_{50}$ are key quantities commonly used in pharmaco-dynamic modelling, yet a comprehensive mathematical investigation of the behaviour of these two metrics is still outstanding; for a large (and important) family of receptors, called cytokine receptors, we still do not know how amplitude and EC$_{50}$ depend on receptor copy numbers. Here we make use of algebraic approaches (Gröbner basis) to study these metrics for a large class of receptor-ligand models, with a focus on cytokine receptors. In particular, we introduce a method, making use of two motivating examples based on the interleukin-7 (IL-7) receptor, to compute analytic expressions for the amplitude and the EC$_{50}$. We then extend the method to a wider class of receptor-ligand systems, sequential receptor-ligand systems with extrinsic kinase, and provide some examples.

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